The goal of this project is to elucidate the function of huntingtin protein, mutation of which underlies Huntingtin's disease (HD). These mutations are expansions of a polyglutamine repeat motif (coded by CAG trinucleotide repeats in the mRNA) within the protein, making HD one of several known "glutamine repeat disorders". In this group of neurodegenerative diseases, an expansion of a polyglutamine repeat in a number of different proteins confers the various disease phenotypes. Transcriptional dysregulation and abnormalities in energy metabolism have been implicated in the pathogenesis of HD. Here we hypothesize that these two processes may be functionally linked in HD. Our preliminary data demonstrates that mutant huntingtin inhibits transcription of coactivator PGC-1a, a major regulator of mitochondrial biogenesis and cellular respiration in several cell types. Increased PGC-1a levels in different tissues lead to enhanced mitochondrial electron transport that enable cells to meet raising energy demands. In this work, we propose to analyze the transcriptional mechanisms by which mutant huntingtin interferes with the function of PGC-1a. Transgenic mice expressing PGC-1a in the brain will be generated and crossed with HD mice to determine whether gain-of-function of PGC-1a alters survival and neuropathology in HD transgenic mice. In addition, mechanisms that lead to modulation of PGC-1a activity in HD will be studied. Upstream regulators controlling PGC-1a transcription in HD cells will be identified to determine whether activation of PGC-1a leads to correction of energy deficits in HD. Target genes of PGC-1a and markers of mitochondrial function will be analyzed in HD cell and tissues. Completion of these aims should reveal new insights into general mechanisms of polyglutamine-induced neurodegeneration and lead to identification of new molecular targets for therapies in HD. [unreadable] PUBLIC HEALTH RELEVANCE: The goal of this project is to elucidate neuroprotective mechanisms in Huntington's disease (HD). We have evidence that disruptions of energy metabolism and deregulation of gene transcription are functionally linked in HD. Our preliminary data suggest that mutant huntingtin represses transcriptional regulation of peroxisome proliferator activator receptor coactivator 1 alpha (PGC-1a). Recent studies have implicated PGC-1a as a major regulator of mitochondrial biogenesis and cellular respiration in several cell types, suggesting that disruption of PGC-1a expression may lead to cellular dysfunction and cell death. We propose a study to search for activators and modulators of PGC-1a expression and activity in HD. Since PGC-1alpha has been implicated in various disorders, including Parkinson's disease, such regulators of PGC-1a function may prove valuable for development of neuroprotective therapies for HD and other neurodegenerative disorders. [unreadable] [unreadable]